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Monday, 01.03.2021

Mogens Schou’s My Journey with Lithium, written on the invitation of Johan Schioldann

Janusz K. Rybakowski’s comment

 

        My comment on the Mogens Schou autobiography, written by Johann Schioldann, is  based on the speech I delivered in Copenhagen, November 23, 2018, when we celebrated the 100th anniversary of Mogens Schou's birthday.

        Mogens Schou was a great clinician and scientist - a true giant of lithium research and treatment.  For the establishment of contemporary lithium therapy, Mogens Schou probably achieved more than anybody in the world. There was more than a half century of his indefatigable lithium activity which he performed with great and exceptional scientific scrutiny. Among lithium researchers, Mogens Schou can be named Primus Inter Pares as he, together with his Danish colleagues, were the first to perform pivotal studies and to make important clinical observations on lithium therapy. Concomitant with this, Mogens Schou was also extremely engaged in the care of patients receiving lithium.

        The year Mogens Schou began his lithium studies, 1952, coincides with the year of the death of his father Hans Jacob Schou, a prominent Danish psychiatrist. From him, Mogens inherited a dedication to patients and to neurobiological studies of psychiatric disorders. The initial fruit of his clinical studies on lithium took place two years later, with the publication of the first controlled study on lithium’s effectiveness among patients in a manic state (Schou, Juel-Nielsen, Strömgren and Voldby 1954).  When it was performed over half a century ago, the study was kind of unusual because the researchers used a neutral preparation (placebo) for comparative purposes to show the "real" effect of lithium. The study included 38 patients in a manic state, among whom 30 had “clear” affective symptoms - a spectacular improvement was noted in 12, improvement in 15 and a lack of effect in three. During therapy, measurements of the concentration of the drug in blood serum were systematically made and in six of them in cerebrospinal fluid. It was found that concentrations of lithium ion in the serum remained within 0.5 to 2 mmol/l, which was an important element for further research on relations between the concentration of lithium in serum and its clinical effectiveness and toxic symptoms. Three years later Mogens Schou summed up in his extensive article published in the Pharmacological Reviews the whole contemporary knowledge concerning pharmacology, biochemistry and clinical effects of lithium (Schou 1957).

        The real breakthrough for the understanding of lithium’s therapeutic action in mood disorders occurred in the early 1960s when the first reports pointing to a possible prophylactic effect of lithium therapy on manic and depressive recurrences appeared. They came from England (Geoffrey Hartigan 2014) and Denmark (Paul Christian Baastrup 1964). In connection with this, Mogens Schou, together with Paul Baastrup, performed a mirror-image study of lithium prophylaxis on 88 patients with unipolar and bipolar affective disorder in Denmark’s Glostrup hospital. The trial lasted six and half years and the main finding was that the average duration of disordered mood (mania or depression) within a year before lithium was 13 weeks, while during a year on lithium it was shortened to the average of two weeks. The results were published in the Archives of General Psychiatry (Baastrup and Schou 1967).

        The next year, 1968, was marked by Mogens Schou’s important clinical observations and studies. For the first time, the adverse effect of lithium on thyroid function (goiter) was described, based on findings in a big group of 330 lithium-treated patients (Schou, Amdisen, Eskjaer et al. 1968a). Also, a study on renal handling of lithium elucidated the mechanism of renal lithium reabsorption (occurring in the proximal tubule) and its relationship to sodium reabsorption. This discovery provided a plausible explanation of lithium toxicity with sometimes fatal outcome in subjects receiving lithium as a salt substitute which occurred in turn of 1940/1950s (Thomsen and Schou 1968). And, based on eight cases, the first comprehensive description of lithium poisoning was published, with a characterization of prodromes, clinical picture and outcomes, as well as suggested management (Schou, Amdisen and Trap-Jensen 1968b).

        However, in the same year, a strong backlash against lithium prophylaxis provided by the British psychiatrists Barry Blackwell and Michael Shepherd appeared in Lancet, titled  “Prophylactic lithium. Another therapeutic myth?” The article was questioned the validity of the findings on lithium effectiveness and requested double-blind trials on this issue (Blackwell and Shepherd 1968). Fifty years after this publication, Barry Blackwell, who initiated INHN discussion on the topic with "The Lithium Controversy. A Historical Autopsy" (2014) seemed to be confident that lithium remains the best first choice for mood stabilization in bipolar disorder.

        Eight placebo-controlled trials in which Mogens Schou exercised a significant initiative were performed in Europe (in Denmark and the UK) and the USA in 1970–1973. In these studies patients were to have had at least two recurrences of illness in the two years preceding lithium treatment. Most of these studies employed a method comparing the course of illness in a group in which lithium was discontinued and replaced with a placebo with a group which continued to receive lithium (discontinuation design). Recurrence of illness was defined as a deterioration that would require psychiatric hospitalization or commencing regular antidepressive or antimanic treatment. Analysis of all research showed that the percentage of patients in whom recurrences of depression or mania occurred was significantly lower while receiving lithium (on average 30%) than while receiving placebo (on average 70%) (Schou and Thomson 1976).

        Because lithium therapy can be administered during pregnancy, Mogens Schou in 1968 helped initiate the “Register of Lithium Babies” (Schou, Goldfield, Weinstein and Villeneuve 1973). The clinical observations to-date have shown that lithium use during pregnancy by women with a mood disorder, especially by those previously treated with this drug, makes a favorable risk/benefit ratio in favor of lithium (Poels, Bijma, Galbally and Bergink 2018).

        In his promulgation of lithium therapy, Mogens Schou was very interested in how such therapy influences the various aspects of the patient’s life. As bipolar disorder is overrepresented among artists, he was the first to examine the issue of the effect of lithium prophylaxis on artistic creativity.  From 24 artists treated with lithium due to bipolar disorder, 12 reported an increase in their artistic productivity, six a slight decrease and six noted no change at all (Schou 1979).

        Schou was extremely dedicated to the best clinical practice of lithium therapy. Since 1980 there have appeared successive issues of Mogens Schou’s book Lithium Treatment of Manic-Depressive Illness, a practical guide to lithium therapy for doctors, patients and their families. Successive revised editions appeared in 1983, 1986, 1988 and 1993. The 6th edition was titled Lithium Treatment of Mood Disorders (Schou 2004).

        Mogens Schou, together with Bruno Müller-Oerlingausen from Berlin, and Paul Grof from Ottawa were the Founding Fathers of the International Group for the Study of Lithium-Treated Patients (IGSLI), created in 1988. In the 1990s the group published seminal papers showing a favorable influence of lithium on the decrease of mortality and prevention of suicidal behaviors (Müller-Oerlinghausen, Ahrens, Volk et al. 1991; Müller-Oerlinghausen, Wolf, Ahrens 1994; Müller-Oerlinghausen, Wolf, Ahrens et al. 1996). Recently, the IGSLI publication confirmed the neuroprotective effect of lithium (Hajek, Bauer, Simhandl et al. 2014). Since its conception, the group has had yearly meetings; the most recent, the 32nd IGSLI conference, took place in Santiago, Chile. There participants could visit the Acatama Dessert, the world's largest and purest active source of lithium.

        In the years 1990-1994 the journal Lithium was published. Mogens Schou was on the editorial board and became the author of the first scientific article in the journal; it was on lithium and treatment-resistant depression (Schou 1990). After many years, lithium augmentation of antidepressants is the best evidenced pharmacological strategy in treatment-resistant depression (Bauer, Adli, Ricken et al. 2014). By some researchers, it is even regarded as the second main indication for lithium use (after preventing mood recurrences) in mood disorders.

        With the foundation in 1999 of the International Society of Bipolar Disorders (ISBD), Mogens Schou was nominated as its honorable president. Since 2001, during the society’s annual international conferences, Mogens Schou’s awards have been given for exceptional achievements in the field of research, educational activity and organizational and media activity concerning the bipolar affective disorder.

        On September 23–25, 2005, Mogens Schou participated in the 19th IGSLI conference that took place in Poznań, Poland. In spite of limitations connected with his advanced age, he was very glad that he could actively participate in this conference; during it, he presented one of his new research proposals. It concerned the issue of lithium for prophylaxis of unipolar depression where he suspected a significant efficacy, especially among so-called "hidden bipolars." Over the years, a growing number of controlled studies have been published confirming that lithium has prophylactic effectiveness in unipolar depression. Recently, it was reported from Finland, on the basis of an observational study, that lithium monotherapy is the pharmacological treatment associated with the lowest risk of psychiatric hospitalization in patients with severe unipolar depression (Tiihonen, Tanskanen, Hoti et al., 2017). There was no sign then that several days after the Poznan IGSLI conference Mogens Schou would finish his busy lithium-oriented life.

        My account of Mogens Schou spanned from 1971, when I wrote the letter to him about my interest in lithium treatment, until the IGSLI conference in Poznan in 2005 when Mogens brought me the copy of this letter as a token of our long-term acquaintance. This was a very emotional event for both of us. In the meantime, I was a Mogens’s student, visiting him on several occasions in Risskov, Denmark. Gradually, I became his partner in lithium research. The crowning achievement of this relationship was the Mogens Schou Research award I received during the International Society of Bipolar Disorder conference in Mexico City held in March 2018.

 

References:

Baastrup PC, Schou M. Lithium as a prophylactic agents. Its effect against recurrent depressions and manic-depressive psychosis. Arch Gen Psychiatry 1967;16:162-72.

Baastrup P.C. The use of lithium in manic-depressive psychoses. Compr Psychiatry 1964; 5:396-408.

Blackwell B, Shepherd M. Prophylactic lithium: another therapeutic myth? An examination of the evidence to date. Lancet 1968;7549:968-71.

Blackwell B. The Lithium Controversy. A Historical Autopsy. inhn.org.controversies. June 19, 2014.

Hajek T, Bauer M, Simhandl C, Rybakowski J, O'Donovan C, Pfennig A et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med 2014;44:507-17.

Hartigan G.P. The use of lithium salts in affective disorders. Br J Psychiatry 1963; 109:810-814.Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs 2014;28:331-42.

Müller-Oerlinghausen B, Ahrens B, Volk J, Grof P, Grof E, Schou M, Vestergåard P, Lenz G, Simhandl C, Thau K, et al. Reduced mortality of manic-depressive patients in long-term lithium treatment: an international collaborative study by IGSLI. Psychiatry Res 1991;36:329-31.

Müller-Oerlinghausen B, Wolf T, Ahrens B, Schou M, Grof E, Grof P, Lenz G, Simhandl C, Thau K, Wolf R. Mortality during initial and during later lithium treatment. A collaborative study by the International Group for the Study of Lithium-treated Patients. Acta Psychiatr Scand 1994;90:295-7.

Müller-Oerlinghausen B, Wolf T, Ahrens B, Glaenz T, Schou M, Grof E, Grof P, Lenz G, Simhandl C, Thau K, Vestergaard P, Wolf R. Mortality of patients who dropped out from regular lithium prophylaxis: a collaborative study by the International Group for the Study of Lithium-treated patients (IGSLI). Acta Psychiatr Scand 1996;94:344-7.

Poels EMP, Bijma HH, Galbally M, Bergink V. Lithium during pregnancy and after delivery: a review. Int J Bipolar Disord 2018;6:26.

Schou M, Amdisen A, Eskjaer Jensen S, Olsen T. Occurrence of goitre during lithium treatment. Br Med J. 1968a;3:710-13.

Schou M, Amdisen A, Trap-Jensen J. Lithium poisoning Am J Psychiatry 1968b;125:520-7.

Schou M, Goldfield MD, Weinstein MR, Villeneuve A. Lithium and pregnancy. I. Report from the Register of Lithium Babies. Br Med J 1973;2:135-6.

Schou M, Thompsen K. Lithium prophylaxis of recurrent endogenous affective disorders. In: Lithium Research and Therapy, Johnson FN, editor. London: Academic Press 1976. pp. 63-84.

Schou M. Artistic productivity and lithium prophylaxis in manic-depressive illness. Br J Psychiatry 1979;135:97-103.

Schou M. Biology and pharmacology of the lithium ion. Pharmacol Rev 1957;9:17-58.

Schou M. Lithium and treatment-resistant depression. A review. Lithium 1990;1:3-8.

Schou M. Lithium Treatment of Mood Disorders. A Practical Guide. Basel: Karger; 2004.

Schou M, Juel-Nielsen N, Strömgren E, Voldby H. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry. 1954;17:250-60.

Thomsen K, Schou M. Renal lithium excretion in man. Am J Physiol 1968;215 823-7.

Tiihonen J, Tanskanen A, Hoti F, Vattulainen P, Taipale H, Mehtälä J, Lähteenvuo M. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry 2017;4:547-53.

 

October 24, 2019